Increased cyclooxygenase-2 (cox-2) expression and activity in a murine model of metastatic breast cancer

Authors

  • Namita Kundu,

    1. Program in Oncology and Department of Pathology, University of Maryland Greenebaum Cancer Center and School of Medicine, Baltimore, MD, USA
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  • Qingyuan Yang,

    1. Program in Oncology and Department of Pathology, University of Maryland Greenebaum Cancer Center and School of Medicine, Baltimore, MD, USA
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  • Russell Dorsey,

    1. Program in Oncology and Department of Pathology, University of Maryland Greenebaum Cancer Center and School of Medicine, Baltimore, MD, USA
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  • Amy M. Fulton

    Corresponding author
    1. Program in Oncology and Department of Pathology, University of Maryland Greenebaum Cancer Center and School of Medicine, Baltimore, MD, USA
    • Dept. of Pathology, U. of Maryland School of Medicine, 10 S. Pine St., Baltimore, MD 21201, USA
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  • The opinions and assertions contained herein are the private views of the authors and are not to be considered as reflecting the views of the United States Department of Defense.

Abstract

Elevated prostaglandin E2 (PGE2) production is a common feature of human malignancies. This activity has often been attributed to increased metabolic activity of the cyclooxygenase enzymes, although a direct comparison of these 2 parameters i.e., prostaglandin production and cox protein expression, is rarely performed in the same malignant tissue. Using a murine model of metastatic breast cancer, we show that PGE2 levels are positively correlated with increased tumorigenic and metastatic potential. Because prostaglandin synthesis is a product of 2 isoforms of the cyclooxygenase enzyme, we examined the expression and activity of both isoforms. All tumor cell lines examined, regardless of phenotype, express both cox-1 and cox-2 proteins in vitro. In contrast to the uniform cox-2 expression in vitro, only tumors resulting from the transplantation of metastatic cell lines express cox-2 in vivo. Cox-1 is detected in both metastatic and nonmetastatic tumors. Thus, this is the first evidence that, in the tumor milieu, cox-2 expression can be regulated differently in metastatic vs. nonmetastatic lesions. Examination of PGE2 synthesis in vitro reveals that nearly complete inhibition of prostaglandin synthesis occurs in the presence of either indomethacin, which inhibits both isoforms, or NS398, which is selective for the cox-2 isoform. Thus, even though cell lines express both isoforms, the majority of the prostaglandin synthesis stems from the activity of the inducible, cox-2 isoform. Likewise, cell growth is inhibited by both indomethacin and NS398 in a dose-dependent manner, albeit at higher drug concentrations than required to ablate PGE2 synthesis. Despite the inhibition of prostaglandin synthesis, the cox-2 enzyme levels (protein and mRNA) were increased by either indomethacin or NS398. © 2001 Wiley-Liss, Inc.

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